DRUGS USED IN ASTHMA: INTRODUCTION

Asthma is characterized clinically by recurrent bouts of coughing, shortness of breath, chest tightness, and wheezing; physiologically by widespread, reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness to inhaled stimuli; and pathologically by lymphocytic, eosinophilic inflammation of the bronchial mucosa.

In mild asthma, symptoms occur only occasionally, as on exposure to allergens or certain pollutants, on exercise, or after a viral upper respiratory infection. More severe forms of asthma are associated with frequent attacks of wheezing dyspnea, especially at night, and may be associated with chronic airway narrowing, causing chronic respiratory impairment.

• The causes of airway narrowing in acute asthmatic attacks include contraction of airway smooth muscle, inspissation of thick, viscid mucus plugs in the airway lumen, and thickening of the bronchial mucosa from edema, cellular infiltration, and hyperplasia of secretory, vascular, and smooth muscle cells.

• PATHOGENESIS OF ASTHMA

• The classic immunologic model of asthma presents it as a disease mediated by reaginic immune globulin (IgE). Foreign materials that provoke IgE production are described as "allergens"; the most common are proteins from house dust mite, cockroach, cat dander, molds, and pollens.

• The tendency to produce IgE antibodies is genetically determined; asthma and other allergic diseases cluster in families. Once produced, IgE antibodies bind to mast cells in the airway mucosa

• The allergen challenge model does not reproduce all the features of asthma. Most asthma attacks are not triggered by inhalation of allergens. They are triggered by viral respiratory infection.

• Some adults with asthma have no evidence of allergic sensitivity to allergens, and even in people with allergic sensitivity, the severity of symptoms correlates poorly with levels of allergen in the atmosphere.

• Moreover, bronchospasm can be provoked by nonallergenic stimuli such as distilled water, exercise, cold air, sulfur dioxide, and rapid respiratory maneuvers.

• The mechanisms underlying bronchial hyperreactivity are somehow related to inflammation of the airway mucosa. The agents that increase bronchial reactivity, such as ozone exposure, allergen inhalation, and infection with respiratory viruses, also cause airway inflammation.

• The increase in reactivity that is associated with the late asthmatic response to allergen inhalation is sustained and, because it is prevented by treatment with an inhaled corticosteroid, is thought to be caused by airway inflammation.

• Whatever the mechanisms responsible for bronchial hyperreactivity, bronchoconstriction itself seems to result not simply from the direct effect of the released mediators but also from their activation of neural or humoral pathways.

• BASIC PHARMACOLOGY OF AGENTS USED IN THE TREATMENT OF ASTHMA

• The drugs most used for management of asthma are adrenoceptor agonists, or sympathomimetic agents (used as "relievers" or bronchodilators) and inhaled corticosteroids (used as "controllers" or anti-inflammatory agents). Their basic pharmacology is presented elsewhere. In this chapter, we review their pharmacology relevant to asthma.

• SYMPATHOMIMETIC AGENTS• The adrenoceptor agonists have several pharmacologic

actions that are important in the treatment of asthma. They relax airway smooth muscle and inhibit release of bronchoconstricting mediators from mast cells.

• They may also inhibit microvascular leakage and increase mucociliary transport by increasing ciliary activity. As in other tissues, the agonists stimulate adenylyl cyclase and increase the formation of intracellular cAMP.

• The best-characterized action of the adrenoceptor agonists in the airways is relaxation of airway smooth muscle. Although there is no evidence for significant sympathetic innervation of human airway smooth muscle, ample evidence exists for the presence of adrenoceptors on airway smooth muscle. In general, stimulation of B2 receptors relaxes airway smooth muscle, inhibits mediator release, and causes tachycardia and skeletal muscle tremor as side effects.

• The sympathomimetic agents that have been widely used in the treatment of asthma include epinephrine, ephedrine, isoproterenol, and albuterol and other B2-selective agents. Because epinephrine and isoproterenol increase the rate and force of cardiac contraction (mediated mainly by B1 receptors), they are reserved for special situations

• In general, adrenoceptor agonists are best delivered by inhalation because this results in the greatest local effect on airway smooth muscle with the least systemic toxicity.

• Aerosol deposition depends on the particle size, the pattern of breathing (tidal volume and rate of airflow), and the geometry of the airways.

• Epinephrine is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff).

• Maximal bronchodilation is achieved 15 minutes after inhalation and lasts 60–90 minutes. Because epinephrine stimulates and B1 as well as B2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are troublesome adverse effects.

• The cardiovascular effects of epinephrine are of value for treating the acute vasodilation and shock as well as the bronchospasm of anaphylaxis, but its use in asthma has been displaced by other, more B2-selective agents

• Ephedrine was used in China for more than 2000 years before its introduction into Western medicine in 1924. Compared with epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and 2-selective agonists, ephedrine is now used infrequently in treating asthma.

• Isoproterenol is a potent bronchodilator; when inhaled as a microaerosol from a pressurized canister, 80–120 mcg isoproterenol causes maximal bronchodilation within 5 minutes. Isoproterenol has a 60- to 90-minute duration of action.

• An increase in the asthma mortality rate that occurred in the United Kingdom in the mid 1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol. It is now rarely used for asthma.

• Beta2-Selective Drugs• The 2-selective adrenoceptor agonist drugs are the most widely

used sympathomimetics for the treatment of asthma at present. These agents differ structurally from epinephrine in having a larger substitution on the amino group and in the position of the hydroxyl groups on the aromatic ring. They are effective after inhaled or oral administration and have a long duration of action.

• Albuterol, terbutaline, metaproterenol, and pirbuterol are available as metered-dose inhalers. Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol.

• Bronchodilation is maximal within 15–30 minutes and persists for 3–4 hours. Because the particles generated by a nebulizer are much larger than those from a metered-dose inhaler, much higher doses must be given (2.5–5.0 mg vs 100–400 mcg) but are no more effective. Nebulized therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler.

• Albuterol and terbutaline are also available in tablet form. One tablet two or three times daily is the usual regimen; the principal adverse effects of skeletal muscle tremor, nervousness, and occasional weakness may be reduced by starting the patient on half-strength tablets for the first 2 weeks of therapy, but this route of administration presents no advantage over inhaled treatment.

• A new generation of long-acting 2-selective agonists includes salmeterol and formoterol. Both drugs are potent selective B2 agonists that achieve their long duration of action (12 hours or more) as a result of high lipid solubility.

• This permits them to dissolve in the smooth muscle cell membrane in high concentrations or, possibly, attach to "mooring" molecules in the vicinity of the adrenoceptor. These drugs appear to interact with inhaled corticosteroids to improve asthma control. They are not recommended as the sole therapy for asthma.

• Toxicities• The use of sympathomimetic agents by inhalation at

first raised fears about possible cardiac arrhythmias and about hypoxemia acutely and tachyphylaxis or tolerance when given repeatedly

• Administration of supplemental oxygen, routine in treatment of an acute severe attack of asthma, eliminates any concern over this effect. The other concern, that -agonist treatment may cause lethal cardiac arrhythmias appears unsubstantiated.

• In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improvewith the improvements in gas exchange effected by bronchodilator treatment

• Fears that heavy use of B-agonist inhalers could actually increase morbidity and mortality have not been borne out by careful epidemiologic investigations. Heavy use most often indicates that the patient should be receiving more effective prophylactic therapy with corticosteroids.

• Although it is true that B2-adrenoceptor agonists appear to be safe and effective bronchodilators for most patients, there is some evidence that the risk of adverse effects from chronic treatment with long-acting agonists may be greater for some individuals, possibly as a function of genetic variants for the receptor.

• METHYLXANTHINE DRUGS

• The three important methylxanthines are theophylline, theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee, respectively).

• The importance of theophylline as a therapeutic agent in the treatment of asthma has waned as the greater effectiveness of inhaled adrenoceptor agents for acute asthma and of inhaled anti-inflammatory agents for chronic asthma has been established, but theophylline's very low cost is an important advantage for economically disadvantaged patients in societies in which health care resources are limited.

• Mechanism of Action

• Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family . Because the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cAMP and, in some tissues, cGMP.

• In an effort to reduce toxicity while maintaining therapeutic efficacy, more selective inhibitors of different isoforms of PDE4 have been developed, particularly for the treatment of chronic obstructive pulmonary disease (COPD).

• Several are now in advanced stages of clinical development, (eg, roflumilast, cilomilast, tofimilast), but at the time of writing, none has been approved for clinical use by the FDA. Although several appear promising, none is entirely free of the major adverse effect of this class of drugs, nausea and vomiting.

• Another proposed mechanism is inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells.

• Pharmacodynamics of Methylxanthines• The methylxanthines have effects on the central nervous system,

kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects.

• CENTRAL NERVOUS SYSTEM EFFECTS• In low and moderate doses, the methylxanthines—especially

caffeine—cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages—eg, 100 mg in a cup of coffee—is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma.

• The larger doses necessary for more effective bronchodilation commonly cause nervousness and tremor in some patients. Very high doses, from accidental or suicidal overdose, cause medullary stimulation and convulsions and may lead to death.

• CARDIOVASCULAR EFFECTS• The methylxanthines have positive chronotropic and inotropic

effects. The higher concentrations (> 10 mol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (> 100 mol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired.

• The clinical expression of these effects on cardiovascular function varies among individuals. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. In large doses, these agents also relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction.

• Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent.

• EFFECTS ON GASTROINTESTINAL TRACT• The methylxanthines stimulate secretion of both gastric acid and

digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.

• EFFECTS ON KIDNEY• The methylxanthines—especially theophylline—are weak

diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically useful.

• EFFECTS ON SMOOTH MUSCLE• The bronchodilation produced by the methylxanthines is the major

therapeutic action in asthma. In addition to their effect on airway smooth muscle, these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown.

• EFFECTS ON SKELETAL MUSCLE• The respiratory actions of the methylxanthines may not be

confined to the airways, for they also strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm in patients with COPD. This effect on diaphragmatic performance—rather than an effect on the respiratory center—may account for theophylline's ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.

• Clinical Use of Methylxanthines• Of the xanthines, theophylline is the most effective

bronchodilator, and it has been shown repeatedly both to relieve airflow obstruction in acute asthma and to reduce the severity of symptoms and time lost from work or school in patients with chronic asthma. Theophylline base is only slightly soluble in water, so it has been administered as several salts containing varying amounts of theophylline base.

• Theophylline should be used only where methods to measure theophylline blood levels are available because it has a narrow therapeutic window, and its therapeutic and toxic effects are related to its blood level. Improvement in pulmonary function is correlated with plasma concentration in the range of 5–20 mg/L.

• Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety occur at concentrations of 15 mg/L in some patients and become common at concentrations greater than 20 mg/L. Higher levels (> 40 mg/L) may cause seizures or arrhythmias; these may not be preceded by gastrointestinal or neurologic warning symptoms.

• The plasma clearance of theophylline varies widely. Theophylline is metabolized by the liver, so usual doses may lead to toxic concentrations of the drug in patients with liver disease

• Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. It is inexpensive, and it can be taken orally.

• Its use, however, also requires occasional measurement of plasma levels; it often causes unpleasant minor side effects (especially insomnia); and accidental or intentional overdose can result in severe toxicity or death.

• For oral therapy with the prompt-release formulation, the usual dose is 3–4 mg/kg of theophylline every 6 hours.Changes in dosage result in a new steady-state concentration of theophylline in 1–2 days, so the dosage may be increased at intervals of 2–3 days until therapeutic plasma concentrations are achieved (10–20 mg/L) or until adverse effects develop.

• ANTIMUSCARINIC AGENTS• Observation of the use of leaves from Datura stramonium for

asthma treatment in India led to the discovery of atropine, a potent competitive inhibitor of acetylcholine at postganglionic "muscarinic" receptors, as a bronchodilator.

• Mechanism of Action• Muscarinic antagonists competitively inhibit the effect of

acetylcholine at muscarinic receptors . In the airways, acetylcholine is released from efferent endings of the vagus nerves, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity .

• Very high concentrations—well above those achieved even with maximal therapy—are required to inhibit the response of airway smooth muscle to nonmuscarinic stimulation.

• Clinical Use of Muscarinic Antagonists• Antimuscarinic agents are effective bronchodilators. When

given intravenously, atropine, the prototypical muscarinic antagonist, causes bronchodilation at a lower dose than that needed to cause an increase in heart rate.

• The selectivity of atropine's effect can be increased further by administering the drug by inhalation or by use of a more selective quaternary ammonium derivative of atropine, ipratropium bromide.

• Ipratropium can be delivered in high doses by this route because it is poorly absorbed into the circulation and does not readily enter the central nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. In some, bronchoconstriction is inhibited effectively; in others, only modestly.

• Although antimuscarinic drugs appear to be slightly less effective than -agonist agents in reversing asthmatic bronchospasm, the addition of ipratropium enhances the bronchodilation produced by nebulized albuterol in acute severe asthma.

• Ipratropium appears to be at least as effective in patients with COPD that includes a partially reversible component.

• A longer-acting, selective antimuscarinic agent, tiotropium, is approved as a treatment for COPD. This drug is also taken by inhalation, and a single dose of 18 mcg has 24-hour duration of action. Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition.

• CORTICOSTEROIDS• Mechanism of Action• Corticosteroids have been used to treat asthma since 1950

and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines .

• Their effect on airway obstruction may be due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of -receptor agonists, but their most important action is inhibition of the lymphocytic, eosinophilic mucosal inflammation of asthmatic airways.

• Clinical Use of Corticosteroids• Clinical studies of corticosteroids consistently show them to

be effective in improving all indices of asthma control—severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life.

• Urgent treatment is often begun with an oral dose of 30–60 mg prednisone per day or an intravenous dose of 1 mg/kg methylprednisolone every 6 hours; the daily dose is decreased after airway obstruction has improved.

• In most patients, systemic corticosteroid therapy can be discontinued in a week or 10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels. For prevention of nocturnal asthma, however, oral or inhaled corticosteroids are most effective when given in the late afternoon.

• Aerosol treatment is the most effective way to avoid the systemic adverse effects of corticosteroid therapy. The introduction of corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone has made it possible to deliver corticosteroids to the airways with minimal systemic absorption.

• A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis. The risk of this complication can be reduced by having patients gargle water and spit after each inhaled treatment. Hoarseness can also result from a direct local effect of inhaled corticosteroids on the vocal cords.

• These agents are remarkably free of other short-term complications in adults but may increase the risks of osteoporosis and cataracts over the long term. In children, inhaled corticosteroid therapy has been shown to slow the rate of growth, but this effect appears to be transient: Asthma itself delays puberty, and there is no evidence that inhaled corticosteroid therapy in childhood influences adult height.

• A novel approach to minimizing the risk of toxicity from systemic absorption of an inhaled corticosteroid underlay the development of ciclesonide.

• When absorbed into the circulation, the active product is tightly bound to serum proteins, and so has little access to glucocorticoid receptors in skin, eye, and bone, minimizing its risk of causing cutaneous thinning, cataracts, osteoporosis, or temporary slowing of growth.

• Chronic use of inhaled corticosteroids effectively reduces symptoms and improves pulmonary function in patients with mild asthma. Such use also reduces or eliminates the need for oral corticosteroids in patients with more severe disease. In contrast to -stimulant agents and theophylline, chronic use of inhaled corticosteroids reduces bronchial reactivity.

• This therapy is continued for 10–12 weeks and then withdrawn to determine whether more prolonged therapy is needed. Inhaled corticosteroids are not curative. In most patients, the manifestations of asthma return within a few weeks after stopping therapy even if they have been taken in high doses for 2 years or longer.

• CROMOLYN & NEDOCROMIL

• Cromolyn sodium (disodium cromoglycate) and nedocromil sodium are stable but extremely insoluble salts.

• When used as aerosols (by nebulizer or metered-dose inhaler), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity.

• However, these drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm; they are only of value when taken prophylactically.

• Cromolyn is poorly absorbed from the gastrointestinal tract and must be inhaled as a microfine powder or aerosolized solution. Nedocromil also has a very low bioavailability and is available only in metered-dose aerosol form.

• Mechanism of Action• Cromolyn and nedocromil differ structurally but are thought

to share a common mechanism of action: an alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation.

• This action on airway nerves is thought to be responsible for nedocromil's inhibition of cough; on mast cells, for inhibition of the early response to antigen challenge; and on eosinophils, for inhibition of the inflammatory response to inhalation of allergens. The inhibitory effect on mast cells appears to be specific for cell type, since cromolyn has little inhibitory effect on mediator release from human basophils.

• This simplistic idea has been overturned in part by the finding that cromolyn and nedocromil inhibit the function of cells other than mast cells and in part by the finding that nedocromil inhibits appearance of the late response even when given after the early response to antigen challenge, ie, after mast cell degranulation has occurred.

• Clinical Use of Cromolyn & Nedocromil

• In short-term clinical trials, pretreatment with cromolyn or nedocromil blocks the bronchoconstriction caused by allergen inhalation, by exercise, by sulfur dioxide, and by a variety of causes of occupational asthma.

• This acute protective effect of a single treatment makes cromolyn useful for administration shortly before exercise or before unavoidable exposure to an allergen.

• In general, young patients with extrinsic asthma are most likely to respond favorably. At present, the only way of determining whether a patient will respond is by a therapeutic trial for 4 weeks. The addition of nedocromil to a standard dose of an inhaled corticosteroid appears to improve asthma control.

• Cromolyn solution is also useful in reducing symptoms of allergic rhinoconjunctivitis. Applying the solution by nasal spray or eye drops several times a day is effective in about 75% of patients, even during the peak pollen season.

• Because the drugs are so poorly absorbed, adverse effects of cromolyn and nedocromil are minor and are localized to the sites of deposition. These include such minor symptoms as throat irritation, cough, and mouth dryness, and, rarely, chest tightness, and wheezing. Some of these symptoms can be prevented by inhaling a 2-adrenoceptor agonist before cromolyn or nedocromil treatment.

• Serious adverse effects are rare. Reversible dermatitis, myositis, or gastroenteritis occurs in less than 2% of patients, and a very few cases of pulmonary infiltration with eosinophilia and anaphylaxis have been reported.

• This lack of toxicity accounts for cromolyn's widespread use in children, especially those at ages of rapid growth. For children who have difficulty coordinating the use of the inhaler device, cromolyn may be given by aerosol of a 1% solution.

• LEUKOTRIENE PATHWAY INHIBITORS• Because of the evidence of leukotriene involvement in

many inflammatory diseases and in anaphylaxis, considerable effort has been expended on the development of drugs that block the synthesis of these arachidonic acid derivatives or their receptors.

• Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and are synthesized by a variety of inflammatory cells in the airways, including eosinophils, mast cells, macrophages, and basophils.

• Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion.

• Two approaches to interrupting the leukotriene pathway have been pursued: inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action. Efficacy in blocking airway responses to exercise and to antigen challenge has been shown for drugs in both categories: zileuton, a 5-lipoxygenase inhibitor, and zafirlukast and montelukast, LTD4-receptor antagonists.

• Their effects on symptoms, airway caliber, bronchial reactivity, and airway inflammation are less marked than the effects of inhaled corticosteroids, but they are more nearly equal in reducing the frequency of exacerbations.

• Their principal advantage is that they are taken orally; some patients—especially children—comply poorly with inhaled therapies. Montelukast is approved for children as young as 6 years of age.

• Some patients appear to have particularly favorable responses, but no clinical features allow identification of "responders" before a trial of therapy. In the USA, zileuton is approved for use in an oral dosage of 400–800 mg for administration 2–4 times daily; zafirlukast, 20 mg twice daily; and montelukast, 10 mg (for adults) or 4 mg (for children) once daily.

• Of these agents, zileuton is the least prescribed because of the former requirement of four-times-daily dosing (a formulation for twice-daily use has recently been developed) and because of occasional liver toxicity.

• The receptor antagonists appear to be safe to use. Reports of Churg-Strauss syndrome (a systemic vasculitis accompanied by worsening asthma, pulmonary infiltrates, and eosinophilia) appear to have been coincidental, with the syndrome unmasked by the reduction in prednisone dosage made possible by the addition of zafirlukast or montelukast.

• OTHER DRUGS IN THE TREATMENT OF ASTHMA

• Anti-IgE Monoclonal Antibodies

• An entirely new approach to the treatment of asthma exploits advances in molecular biology to target IgE antibody.

• Omalizumab (an anti-IgE monoclonal antibody) inhibits the binding of IgE to mast cells but does not activate IgE already bound to these cells and thus does not provoke mast cell degranulation.

• It may also inhibit IgE synthesis by B lymphocytes. The murine antibody has been genetically humanized by replacing all but a small fraction of its amino acids with those found in human proteins, and it does not appear to cause sensitization when given to human subjects.

• Studies of omalizumab in asthmatic volunteers showed that its administration over 10 weeks lowered plasma IgE to undetectable levels and significantly reduced the magnitude of both the early and the late bronchospastic responses to antigen challenge. Omalizumab's most important effect is reduction of the frequency and severity of asthma exacerbations, even while enabling a reduction in corticosteroid requirements.

• Possible Future Therapies• The rapid advance in the scientific description of the

immunopathogenesis of asthma has spurred the development of many new therapies targeting different sites in the immune cascade.

• These include monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13), antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 phenotype or at selective inhibition of the subset of TH2 lymphocytes directed against particular antigens.

• There is evidence that asthma may be aggravated—or even caused—by chronic airway infection with Chlamydia pneumoniaeor Mycoplasma pneumoniae. This may explain the reports of benefit from treatment with macrolide antibiotics and, if confirmed, would stimulate the development of new diagnostic methods and antimicrobial therapies.

• CLINICAL PHARMACOLOGY OF DRUGS USED IN THE TREATMENT OF ASTHMA

• Asthma is best thought of as a disease in two time domains. In the present domain, it is important for the distress it causes—cough, nocturnal awakenings, and shortness of breath that interferes with the ability to exercise or to pursue desired activities.

• For mild asthma, occasional inhalation of a bronchodilator may be all that is needed. For more severe asthma, treatment with a long-term controller, like an inhaled corticosteroid, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations, or of progressive loss of pulmonary function.

• For relief of distress in the present domain, the key information can be obtained by asking specific questions about the frequency and severity of symptoms, the frequency of use of an inhaled 2agonist for relief of symptoms, the frequency of nocturnal awakenings, and the ability to exercise

• BRONCHODILATORS• Bronchodilators, such as inhaled albuterol, are rapidly

effective, safe, and inexpensive. Patients with only occasional symptoms of asthma require no more than an inhaled 2-receptor agonist taken on an as-needed basis.

• If symptoms require this "rescue" therapy more than twice a week, if nocturnal symptoms occur more than twice a month, or if the FEV1 is less than 80% predicted, additional treatment is needed. The treatment first recommended is a low dose of an inhaled corticosteroid, although treatment with a leukotriene receptor antagonist or with cromolyn may be used.

• Theophylline is now largely reserved for patients in whom symptoms remain poorly controlled despite the combination of regular treatment with an inhaled anti-inflammatory agent and as-needed use of a 2 agonist.

• MUSCARINIC ANTAGONISTS• Inhaled muscarinic antagonists have so far earned a limited

place in the treatment of asthma. When adequate doses are given, their effect on baseline airway resistance is nearly as great as that of the sympathomimetic drugs.

• The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in patients with severe airflow obstruction who present for emergency care.

• Antimuscarinic agents appear to be of greater value in COPD—perhaps more so than in asthma. They are also useful as alternative therapies for patients intolerant of 2-adrenoceptor agonists. The drugs do, however, inhibit the increase in mucus secretion caused by vagal stimulation. No cases of inspissation of mucus have been reported following administration of these drugs.

• CORTICOSTEROIDS

• If asthmatic symptoms occur frequently or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started.

• For patients with severe symptoms or severe airflow obstruction (eg, FEV1 < 50% predicted), initial treatment with a combination of inhaled and oral corticosteroid (eg, 30 mg/d of prednisone for 3 weeks) treatment is appropriate. Once clinical improvement is noted, usually after 7–10 days, the oral dose should be discontinued or reduced to the minimum necessary to control symptoms.

• An issue for inhaled corticosteroid treatment is patient compliance. Analysis of prescription renewals shows that corticosteroids are taken regularly by a minority of patients.

• In patients with more severe asthma, whose symptoms are inadequately controlled by a standard dose of an inhaled corticosteroid, two options may be considered: to double the dose of inhaled corticosteroid or to add a long-acting inhaled 2-receptor agonist (salmeterol or formoterol).

• Many studies have shown this combination therapy to be more effective than doubling the dose of the inhaled corticosteroid, but the FDA has issued a warning that the use of a long-acting agonist is associated with a very small but statistically significant increase in the risk of death or near death from an asthma attack, especially in African Americans.

• This warning has not so far had much effect on prescriptions for a fixed-dose combination of inhaled fluticasone (a corticosteroid) and salmeterol (a long-acting agonist), probably because their combination in a single inhaler offers several advantages

• CROMOLYN & NEDOCROMIL; LEUKOTRIENE ANTAGONISTS• Cromolyn or nedocromil by inhalation, or a leukotriene-

receptor antagonist as an oral tablet, may be considered as alternatives to inhaled corticosteroid treatment in patients with symptoms occurring more than twice a week or who are wakened from sleep by asthma more than twice a month.

• Cromolyn and nedocromil may also be useful in patients whose symptoms occur seasonally or after clear-cut inciting stimuli such as exercise or exposure to animal danders or irritants.

• Treatment with a leukotriene-receptor antagonist, particularly montelukast, is widely prescribed, especially by primary care providers. Taken orally, leukotriene-receptor antagonists are easy to use and appear to be taken more regularly than inhaled corticosteroids. They are rarely associated with troublesome side effects.

• ANTI-IGE MONOCLONAL ANTIBODY• Treatment with omalizumab, the monoclonal humanized anti-

IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting -agonist combination treatment (eg, fluticasone 500 mcg plus salmeterol 50 mcg inhaled twice daily).

• This treatment reduces lymphocytic, eosinophilic bronchial inflammation and effectively reduces the frequency and severity of exacerbations.

• OTHER ANTI-INFLAMMATORY THERAPIES• Some reports suggest that agents commonly used to treat

rheumatoid arthritis may also be used to treat patients with chronic steroid-dependent asthma. An immunomodulatory therapy recently reported to improve asthma is injection of etanercept, a TNF- antagonist used for treatment of ankylosing spondylitis and severe rheumatoid arthritis.

• MANAGEMENT OF ACUTE ASTHMA• The treatment of acute attacks of asthma in patients

reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of lung function. For patients with mild attacks, inhalation of a 2-receptor agonist is as effective as subcutaneous injection of epinephrine.

• Both of these treatments are more effective than intravenous administration of aminophylline (a soluble salt of theophylline). Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6 hours).

• General anesthesia, intubation, and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes.

• PROSPECTS FOR PREVENTION• The high prevalence of asthma in the developed world

and its rapid increases in the developing world call for a strategy for primary prevention.

• Strict antigen avoidance during infancy, once thought to be sensible, has now been shown to be ineffective. In fact, growing up in a household where cats and dogs are kept as pets may protect against developing asthma.

• The best hope seems to lie in understanding the importance of microbial exposures during infancy in shaping a balanced immune response, and one study showing that feeding Lactobacillus caseii to infants born to allergic parents reduced the rate of allergic dermatitis at age 2 years offers reason for hope.

• Treatment recommendations based on:– Severity

– Control

– Responsiveness

• Provide patient self-management education at multiple points of care

• Reduce exposure to inhaled indoor allergens to control asthma-multifaceted approach

Source: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

Six Key Messages in asthma

• Inhaled

Corticosteroids

• Asthma Action Plan

• Asthma Severity

• Asthma Control

• Follow-up Visits

• Allergen and Irritant

Exposure Control

Source: http://www.nhlbi.nih.gov/guidelines/asthma/gip_rpt.pdf

Diagnosing Asthma:

Medical History

• Symptoms– Coughing

– Wheezing

– Shortness of breath

– Chest tightness

• Symptom Patterns

• Severity

• Family History

Diagnosing Asthma

• Troublesome cough, particularly at night

• Awakened by coughing

• Coughing or wheezing after physical

activity

• Breathing problems during particular

seasons

• Coughing, wheezing, or chest tightness

after allergen exposure

• Colds that last more than 10 days

• Relief when medication is used

Diagnosing Asthma

• Wheezing sounds during normal breathing

• Hyperexpansion of the thorax

• Increased nasal secretions or nasal polyps

• Atopic dermatitis, eczema, or other allergic skin conditions

Diagnosing Asthma:

Spirometry

Test lung function when diagnosing asthma

Medications to Treat Asthma:

Long-Term Control

• Taken daily over a long period of time

• Used to reduce inflammation, relax airway

muscles, and improve symptoms and lung

function

– Inhaled corticosteroids

– Long-acting beta2-agonists

– Leukotriene modifiers

Medications to Treat Asthma:

How to Use a Spray Inhaler

The health-care provider should evaluate inhaler technique at each visit.

Source: “What You and Your Family Can Do About Asthma” by the Global Initiative for Asthma Created and funded by NIH/NHLBI

Medications to Treat Asthma:

Nebulizer

• Machine produces a mist of the medication

• Used for small children or for severe asthma episodes

• No evidence that it is more effective than an inhaler used with a spacer

Selective estrogen receptor modulators, called SERMs for short, block the effects of estrogen in the breast tissue.

SERMs work by sitting in the estrogen receptors in breast cells. If a SERM is in the estrogen receptor, there is no

room for estrogen and it can't attach to the cell. If estrogen isn't attached to a breast cell, the cell doesn't

receive estrogen's signals to grow and multiply.Cells in other tissues in the body, such as bones and the uterus, also have estrogen receptors. But each estrogen receptor has a slightly different structure, depending on the kind of cell it is in. So breast cell estrogen receptors

are different from bone cell estrogen receptors and both of those estrogen receptors are different from uterine

estrogen receptors. As their name says, SERMs are "selective" – this means that a SERM that blocks

estrogen's action in breast cells can activate estrogen's action in other cells, such as bone, liver, and uterine cells.

There are three SERMs:• 1)tamoxifen in pill form (also called tamoxifen citrate; brand

name: Nolvadex);tamoxifen in liquid form (brand name: Soltamox)

• 2)Evista raloxifene) 3) Fareston (chemical name: toremifene)• Each is a pill, usually taken once a day, except for tamoxifen in

liquid form. Tamoxifen is the oldest, most well-known, and most-prescribed SERM.

• SERMs can be used to treat women both before and after menopause.

• Benefits of SERMs• Because tamoxifen is the most commonly used SERM, most

of the studies comparing SERMs to aromatase inhibitors have looked at tamoxifen versus aromatase inhibitors. Several studies have compared tamoxifen with aromatase inhibitors to see which type of medicine was more effective in treating early-stage, hormone-receptor-positive breast cancer in postmenopausal women. Based on the results, most doctors go by the following recommendations:

• An aromatase inhibitor is the best type of hormonal therapy to start with for postmenopausal women. When treating early-stage, hormone-receptor-positive breast cancer, aromatase inhibitors have more benefits and fewer serious side effects than tamoxifen.

• Switching to an aromatase inhibitor after taking tamoxifen for 2 to 3 years (for a total of 5 years of hormonal therapy) offers more benefits than 5 years of tamoxifen. Taking an aromataseinhibitor for 5 years after taking tamoxifen for 5 years continues to reduce the risk of the cancer coming back, compared to no treatment after tamoxifen.

• Taking an aromatase inhibitor for 5 years after taking tamoxifen for 5 years continues to reduce the risk of the cancer coming back, compared to no treatment after tamoxifen.

• For premenopausal women diagnosed with hormone-receptor-positive breast cancer, the SERM tamoxifen is the hormonal therapy treatment standard.

• Side effects of SERMs

• SERMs may cause some serious side effects, including blood clots, stroke, and endometrial cancer. If you and your doctor are considering tamoxifen or another SERM as part of your treatment plan, tell your doctor if you smoke or have a history of blood clots or heart attack. If you're taking a SERM, call your doctor immediately if you have any of these symptoms:

• abnormal vaginal bleeding or discharge

• pain or pressure in the pelvis

• leg swelling or tenderness

• chest pain

• shortness of breath

• weakness, tingling, or numbness in your face, arm, or leg

• sudden difficulty seeing

• dizziness

• sudden severe headache

The most common side effects of SERMs are:• fatigue• hot flashes• night sweats• vaginal discharge• mood swingsYou should not take a SERM if you are breastfeeding, pregnant,

trying to get pregnant, or if there is any chance that you could be pregnant. These medicines may cause damage to developing embryos. You should use an effective non-hormonal type of birth control -- such as condoms, a diaphragm along with spermicide, or a non-hormonal I.U.D. –while you are taking a SERM. Ask your doctor which type of non-hormonal birth control would be best for you, as well as how long you should use this type of birth control after you stop taking a SERM.

• As a benefit, SERMs also can improve bone density, which reduces the risk of osteoporosis.